Modulation of Inflammatory Response to Implanted Biomaterials Using Natural Compounds

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Current Pharmaceutical Design, 2017, 23, 1-12 1
REVIEW ARTICLE
Modulation of Inflammatory Response to Implanted Biomaterials Using Natural
Compounds
Maria Yanez1, James Blanchette2 and Ehsan Jabbarzadeh*1,2,3
1Department of Chemical Engineering, University of South Carolina, Columbia, SC 29208, USA ;2Biomedical Engineering Program,
University of South Carolina, Columbia, SC 29208, USA; 3Department of Orthopedic Surgery, University of South Carolina School of
Medicine, Columbia SC, 29209, USA
Abstract: Tissue engineering offers a promising strategy to restore injuries resulting from trauma, infection,
tumor resection, or other diseases. In spite of significant progress, the field faces a significant bottleneck; the
critical need to understand and exploit the interdependencies of tissue healing, angiogenesis, and inflammation.
A R T I C L E H I S T O R Y Inherently, the balance of these interacting processes is affected by a number of injury site conditions that repre-
sent a departure from physiological environment, including reduced pH, increased concentration of free radicals,
Received: January 28, 2016 hypoglycemia, and hypoxia. Efforts to harness the potential of immune response as a therapeutic strategy to pro-
Accepted: April 28, 2017 mote tissue repair have led to the identification of natural compounds with significant anti-inflammatory proper-

ties. This article provides a concise review of the body’s inflammatory response to biomaterials and describes the
DOI: role of oxygen as a physiological cue in this process. We proceed to highlight the potential of natural compounds
10.2174/1381612823666170510124348 to mediate inflammatory response and improve host-graft integration. Herein, we discuss the use of natural com-
pounds to map signaling molecules and checkpoints that regulate the cross-linkage of immune response and
skeletal repair.
Keywords: Inflammatory response, biomaterials, angiogenesis, tissue engineering, macrophages, natural compounds.
interleukin 6 (IL-6), granulocyte-colony stimulating factor (G-
1. INTRODUCTION
CSF), and granulocyte macrophage colony stimulating factor (GM-
The field of tissue engineering has utilized biocompatible mate- CSF) [16-18]. If acute inflammation is not resolved, biomaterial
rials to synthesize scaffolds with optimal chemical and mechanical adherent M1 macrophages will begin to form foreign body giant
properties, in addition to low-level cytotoxicity [1-4]. However, cells, and the acute inflammation becomes chronic inflammation
these efforts have been confounded by the host reaction after im- [18].
plantation. Most implanted biomaterials trigger an initial inflamma-
It is generally believed that three types of macrophages (M0,
tory response due to the host tissue reaction [5]. Inflammation is the
M1, and M2) are involved during different phases of wound healing
body’s response to injury or foreign materials, and is present in
[19]. These macrophages can be polarized by cytokines to differen-
numerous diseases, such as rheumatoid arthritis, infection, and can-
tiate from one phenotype to another [2]. M1 macrophages (pro-
cer [6-8]. As demonstrated in Figure 1A, following the implantation
inflammatory) are present in the early stage of inflammation and
of a material, the wound healing process begins with the recruit-
are activated by foreign agents, such as microbes, necrosis, and/or
ment of neutrophils (polimorphonuclear leukocytes) to the injured
tissue injury [13, 17]. It is hypothesized that M1 macrophages are
site to remove bacteria and foreign bodies by phagocytosis [9-11].
subsequently differentiated to M2 macrophages (anti-inflammatory)
To accelerate the phagocytosis process, neutrophils generate reac-
to continue the wound-healing process [20, 21]. M1 macrophages
tive oxygen species (ROS) which sometimes can cause tissue dam-
express a number of pro-inflammatory cytokines, including TNF-α,
age [11, 12]. These cells are responsible for producing inflamma-
IL-1β, IL-6, IL-12, and IL-23, as well as chemokines such as CXC
tory mediators that later recruit and differentiate monocyte to M0
ligand motif 2 (CXL2), -9, -10, -11, -12, CC-motif ligand 2
macrophages followed by polarization to M1 pro-inflammatory and
(CCL2), -3, -4, and -5, and inducible nitric oxide synthase (iNOS)
M2 pro-healing macrophages. (Figure 1B). If the host integration is
[22]. In contrast, M2 macrophages express anti-inflammatory
not properly orchestrated, chronic inflammation, inadequate angio-
agents including IL-10, along with scavenger, mannose, and galac-
genesis, and biomaterial/device fibrous encapsulation can lead to
tose receptors [23]. There are multiple sub-types of M2 macro-
transplant failure (Figure 1C). Therefore, for tissue engineering
phages, which are distinguished from each other according to their
strategies to be successful, it is vital to control biomaterial-host
function: M2a macrophages (alternatively activated macrophages)
tissue processes interaction [2, 13, 14]. This requires a thorough
are activated by IL-4, whereas M2c macrophages (activated regula-
understanding of the mechanisms by which physiological cues
tory macrophages) are activated by immune complexes, glucocorti-
regulate the interaction of inflammatory cells to biomaterials [13-
coids, prostaglandins, and IL-10 [24-26].
15].
Inflammation is mediated by various enzymes; amongst which,
Inflammatory response progresses through adherence of macro-
the cyclo-oxygenase (COX) is the most extensively studied. COX-1
phages to implanted materials secreting growth factors, such as
and COX-2 play critical roles during the transformation of arachi-
fibroblast growth factor (FGF), vascular endothelial growth factor
donic acid in prostaglandins [27, 28]. The overexpression of COX2
(VEGF), cytokines, including tumor necrosis factor alpha (TNF-α),
and prostaglandin is generated by several pro-inflammatory media-

tors, such as IL-1, IL-6, and TNF-α, and is related to fibrosis encap-
*Address correspondence to this author at the Associate Professor of sulation, scar formation, and delayed wound healing [29, 30]. Due
Chemical Engineering, Associate Professor of Biomedical Engineering,
to its role, COX2 has been used in drug discovey studies aimed at
Associate Professor of Orthopedic Surgery. University of South Carolina,
the modulation of inflammation. Currently, there are different non-
Columbia, SC 29208; Tel: [phone]; Fax: [phone];
steroidal anti-inflammatory drugs such as celecoxib and indometha-
E-mail: [email protected]

1381-6128/17 $58.00+.00 © 2017 Bentham Science Publishers
2 Current Pharmaceutical Design, 2017, Vol. 23, No. 00 Yanez et al.

Fig. (1). Biomaterial host interaction. A) Host reaction after biomaterial implantation where neutrophils migrate to the wound site, and monocytes differentiate
into M1 macrophages (acute inflammation). Hypoxia can trigger the expression of pro-inflammatory cytokines helping the transition from M1 to M2 macro-
phages. B) Pro-healing, normal wound healing process where monocytes are polarized to M2 macrophages. The addition on natural compounds (NC) help to
improve the inflammation process when they target pro-inflammatory mediators including IFN-γ, IL-6, TNF-α, and IL-1β. C) Chronic inflammation, normal
inflammatory respond fails, and pro-inflammatory mediators are over express. M0 macrophages are polarized to M1 macrophages and fibroblast migrate to the
device generating fibrosis.

cin that block COX2 and create an anti-inflammatory effect [31, Inflammation is associated with a number of conditions that
32]. In addition to this, other natural compounds, such as flavon- represent a departure from physiological environment, including
oids, have been tested to reduce cytokine production and inhibit reduced pH, an increased concentration of free radicals, hypogly-
COX2 overproduction [28]. cemia, and hypoxia. The relationship between oxygen partial pres-
Microbubbles: A Novel Strategy for Chemotherapy Current Pharmaceutical Design, 2017, Vol. 23, No. 00 3
sure and inflammation is difficult to characterize due to the com- can cause loss of cells, and in turn impaired organ function, due to
plex interplay of numerous signaling pathways. A departure from apoptosis or even initiate oncogenesis.
physiological oxygen tension in either direction (hypoxia or hyper- Hyperoxia can elevate levels of ROS, and this has been studied
oxia) can alter gene expression and impact cellular behavior with
in neonatal infants placed in high oxygen incubators and in the
the consequences of initiating or augmenting inflammation. Addi- epithelial lining of the lung during hyperoxia [46]. Such conditions
tional information regarding the impact of hyperoxia on inflamma- are less relevant in the immediate vicinity of implanted biomateri-
tion can be found in a number of recent reviews [33, 34]. In the
als. Hypoxia is also linked with ROS generation, in which mito-
context of tissue repair, reduced oxygen levels are more relevant chondrial function plays an essential role. Numerous studies have
due to the damage to the vasculature at an injury site. In addition, shown the necessity of mitochondrial activity for ROS-mediated
because the establishment of a mature vascular network that can
HIF-1a stabilization [47, 48]. This causes elevated expression of
return the local oxygen tension to physiological levels is a process HIF target genes and a further increase in ROS levels. These studies
that takes weeks, the impact of the hypoxic conditions on the in- also identify potential therapeutic targets to reduce the impact of
flammatory response will be chronic rather than acute.
inflammation on HIF stabilization through ROS. A recent review
Alterations in local oxygen tension can be translated into a summarizes many of these phenomena [49, 50].
change in cell phenotype through numerous mechanisms, but the
hypoxia-inducible factor (HIF) family of transcription factors is 2. CONVENTIONAL SYNTHETIC DRUGS TO SUPPRESS
often referred to as the master regulator of this process [35, 36]. INFLAMMATORY RESPONSE
HIFs are heterodimers formed between oxygen-sensitive alpha The interest in effective mitigation of fibrous capsul formation
subunits (HIF-1α and HIF-2α) and a constitutively expressed beta has led to development of steroidal and nonsteroidal classes of anti-
subunit (HIF-1β, also referred to as ARNT). HIF-1α degradation is inflammatory drugs. In this context, corticosteroids (e.g. dex-
tied to cellular oxygen tension. As the oxygen levels drop below amethasone) or glucocorticoids are most commonly used in clinical
6% (~47 mm Hg), HIF-1α expression increases and its proteasomal studies to mimic the functions of anti-inflammatory hormones [51].
degradation decreases. This change allows dimerization with the Recent in vivo experiments demonstrated that augmenting
beta subunit, interaction with the coactivator CREB-binding pro- poly(lactic-co-glycolic acid) (PLGA) scaffolds with dexamethasone
tein, and regulation of the transcription of genes with hypoxia- improved bone regeneration and reduced inflammation. However,
responsive elements in their promoter regions [37]. other studies have found that this improvement was sustained for
HIF activity impacts immune cell phenotypes by triggering the only 4 days and corticosteroids induced a negative side-effect on
expression of IL-1, IL-6, iNOS, TNF-α, and a host of other pro- bone homeostasis and density as well as metabolic system interfer-
inflammatory cytokines. Regulatory T cells (T ) require HIF activ- ence [13, 52].
reg
ity for function, but when HIF activity is elevated by genetic modi- A number of antibodies and biologic agents (e.g. infliximab,
fication, the Treg function in a colitis model is impaired [38]. Simi- adalimumab, etanercept, golimumab, certolizumab-pegol, anakinra,
larly, HIF activity is essential for cytotoxic T lymphocytes (CTL) and tocilizumab, which antagonize IL-1 and IL-6) have been used
[39]. HIF activity mediates their elevated glycolysis, differentiation, to treat chronic inflammation by targeting and inhibiting inflamma-
and enhanced granzyme B levels. These results indicate that any tory cytokines including TNF-α, IL-1, and IL-6. A drawback with
perturbation from baseline activity can initiate a cascade with wide- the use of these inhibitors is the increased risk of infection associ-
ranging consequences. ated with orthopedic surgical implantation [52].
The impacts of hypoxia and elevated HIF activity on the pheno- Non-steroidal anti-inflammatory drugs (NSAIDs) have also
types of macrophages are complex due to the interplay of numerous been used to modulate inflammatory response. Examples of such
pathways. Conclusions regarding the impact of hypoxia on macro- biological agents include ibuprofen, aspirin, naproxen sodium,
phage polarity remain somewhat muddled. While oxygen levels can celecoxib, and COX2 inhibitors. These types of drugs often target
be manipulated easily outside the body, hypoxia is often accompa- the cyclooxygenase enzymes [52].In general, COX inhibitors are
nied by reduced pH, increased concentrations of free radicals, and responsible for the conversion of arachidonic acid to prostagland-
hypoglycemia in vivo. Hypoxia is also used to describe a wide ins. However, studies performed in animal models revealed that
range of oxygen levels; it is expected that macrophages, like other these medications affect bone healing by reducing the bone mineral
cell types, will show different behaviors in 5, 1 and 0.1% oxygen density and mechanical strength in the injured area. Despite limited
environments, which is further complicating the goal of reaching success, NSAIDs provide short-term relief and do not target the real
consensus [40]. The majority of studies have indicated that hypoxia problem causing the inflammation. [51, 53].
and HIF activity promote the M1 to M2 transition, which has been
summarized in previous review articles [41, 42]. Macrophages have 3. NATURAL ANTI-INFLAMMATORY COMPOUNDS TO
the capacity to switch to anaerobic respiration in low-oxygen envi- MODULATE INFLAMMATORY RESPONSE
ronments. In a study that investigated glioblastoma multiforme, Over the years, natural supplements have been commonly used
hypoxic conditions led to elevated macrophage migration and dif- to improve health and to reduce effects associated with aging. Natu-
ferentiation of both M0 and M1 macrophages to the M2 phenotype, ral products can serve as multi-target drugs and thereby improve
as indicated by iNOS and arginase 1 (Arg1) staining [41]. A study more than one health problem. These supplements are extracted
of intermittent hypoxia (IH) found that resveratrol could reduce the from various plants, fruits, and herbs and have been used for many
macrophage migration triggered by low oxygen [43]. It is worth years as remedies. Lately, these types of compounds are becoming
noting that this study also showed a shift in the macrophage pheno- more popular in modern medicine due to their ability to block or
type towards the M1 form, although this shift could have been the activate multiple pathways. These extracts include flavonoids,
result of differences between IH and chronic hypoxia. triterpenes, and polyphenols, to name a few. In the following, we
Reactive oxygen species (ROS) are generated as part of the provide a brief review of in vitro and in vivo investigations that
inflammatory response and levels are altered depending on local used different forms of natural compounds to combat inflammatory
oxygen tension [44, 45]. ROS can react with, and alter, essential diseases.
macromolecules in cells such as proteins and nucleic acids. While
generation of ROS is the result of oxidative phosphorylation, and 3.1. Polyphenols
therefore occurring in mitochondria of healthy cells, departures Polyphenols have garnered a great deal of interest due to their
from physiological levels can overwhelm antioxidant capacity. This ability to reduce arthritic damage through their anti-inflammatory
and anti-oxidant properties [54, 55]. Recent in vitro and in vivo
4 Current Pharmaceutical Design, 2017, Vol. 23, No. 00 Yanez et al.
studies have shown that polyphenols down-regulate pro- preventive, pro-apoptotic, anti-angiogenic, and anti-inflammatory
inflammatory cytokines, stimulate anti-inflammatory agents, in- properties [8, 69]. Its anti-oxidant properties are associated with the
crease forkhead box P3 (Foxp3)-expression in CD4+ regulatory T- inhibition of the nitrite-induced oxidation of hemoglobin [70]. The
cells, and prevent bone loss [56]. In the following, we review the antioxidant effect of curcumin is highly potent due to its multiple
promising application of several polyphenols in studies aimed at functional groups (B-diketo group, carbon–carbon double bonds,
modulation of inflammation. and phenyl rings containing various amounts of hydroxyl and
methoxy substituents) [71].
3.1.1. Resveratrol
The mechanism of action of curcumin during inflammation is
Resveratrol is a natural polyphenol found in various plants in-
related to the suppression of pro-inflammatory pathways (nuclear
cluding grapes, nuts, and berries among which the skin of red
factor erytroid-2 related factor-1, Nrf2-keap 1, and NF- κB) and the
grapes have the highest concentration [57]. Its chemical structure
down-regulation of several cytokines including TNF-α, IL-1, IL-6,
has two phenolic rings bonded together by a double styrene bond,
IL-8, and IL-12 in various cell types [70-75]. Studies performed in
which is responsible for the isometric cis- and trans-forms of res-
rats that were positive for inflammatory markers showed significant
veratrol [58]. Resveratrol has attracted much attention over the
suppression of TNF-α, C-reactive protein (CRP), and COX2 [76].
years for its ability to modulate various pathways associated with
Consistent with these findings, studies performed with colon cancer
cell growth, apoptosis, cancer, and inflammation [59]. In addition,
cells (HT29 and SW480) showed a down-regulation of COX2 and
recent studies have demonstrated resveratrol to be effective in anti-
inhibition of prostaglandin-E2 (PEG2) when exposed to curcumin
aging, anti-oxidant, anti-tumor, anti-platelet aggregation, and anti-
[77]. The in vivo studies by Miao et al. showed that in rats sub-
atherogenic studies [7, 60-64].
jected to an induced middle cerebral artery occlusion, curcumin
Resveratrol has anti-inflammatory properties due to its inhibi-
administration by intraperitoneal injections for 5 days led to TNF-α
tory effect on the expression of mediators including IL-1β, matrix
and IL-6 down-regulation [78]. In addition, the oral administration
metallopeptidase 13 (MMP-13), and COX2 [13, 60, 62]. The
of curcumin has led to reduced inflammation in patients with ul-
mechanism of action of resveratrol is not completely understood,
cerative proctitis and Crohn’s disease as well as accelerated wound
but current research suggests that resveratrol activates the silent
healing [79].
information regulator T1 (SIRT1) protein in the cells which helps to
Curcumin blocks the adhesion of monocytes to endothelial cells
reduce pro-inflammatory cytokines by cutting down nuclear factor
which suppresses tumor vascularization, a process essential for
kappa B (NF- κB).
tumor metastasis [70]. Clinical research with osteoarthritis patients
The tissue engineering community has utilized resveratrol to
has shown that a curcumin-phospatidylcholine complex reduces the
modulate inflammatory response to biomaterials. Resveratrol en-
oxidative stress, down-regulates IL-1β, IL-6, and improves pain and
capsulated in specific scaffolds for local delivery potently down-
various osteoarthritis symptoms [72]. Another interesting study was
regulated TNF-α and IL-1β and suppressed COX2 while blocking conducted by Sun et al. to encapsulate the curcumin into exosome
NF-κB activation [62, 65]. Cellular analysis revealed that resvera-
nanoparticles in order to increase its solubility and induce lipopoly-
trol encapsulated in PLGA nanoparticles reduced the expression of
saccharide (LPS) [8, 69, 79]. Curcumin has been also encapsulated
pro-inflammatory agents (IL-6 and TNF-α), whereas it increased
in pH-sensitive nanoparticles to decrease neutrophil infiltration and
the expression of anti-inflammatory genes including IL-10 and
reduce TNF-α [80].
vascular endothelial growth factor (VEGF), which promoted os-
Although more research is called for, the immune modulatory
teogenesis as demonstrated by alkaline phosphate (ALP) expression
property of curcumin renders it as an inexpensive, natural choice in
in mesenchymal stem cells (MSC). In a recent discovery, resvera-
tissue engineering applications [81-83]. Nevertheless, its short bio-
trol-polyacrylic acid particles were utilized in an atelocollagen ma-
logical life, low absorption, and fast metabolism have hampered the
trix to enhance cyto-compatibility, proliferation and cell viability of
enthusiasm for its use in clinical applications [84]. In spite of these
marrow stromal cells. In addition, the authors found that these scaf-
limitations, further explorations to design novel curcumin formation
folds down-regulated IL-1β, COX2, and MMP-13 [65]. The in vivo
derivatives to enhance systemic bioavailability and efficacy are
data obtained in a rabbit osteochondral defect model showed that a
needed for future human use.
resveratrol-poly(acrylic acid)-collagen hydrogel increased bone and
cartilage gene expression. In another study, Elmali et al. evaluated 3.1.3. Green tea (Camellia sinenesis)
the effect of resveratrol in rabbits with induced arthritis by injecting
Green tea (Camellia sinenesis) contains the major polyphenolic
resveratrol in the affected area. The authors observed that resvera- compounds epigallocatechin-3 galate (EGCG) and flavonoids. Evi-
trol decreased the cartilage damage and inflammation [62]. These
dence in literature suggest that the bioactive compounds of green
studies demonstrate the potential of resveratrol to be used as an
tea prevent cardiovascular problems, cancer, inflammation, and
anti-inflammatory natural molecule which can also enhance tissue neurodegenerative problems due to its anti-oxidant and anti-
integration.
inflammatory properties [85-89]. Several studies have examined the
Resveratrol has demonstrated a dose response effect in various mechanism of action of the green tea components in the improve-
clinical, in vitro, and in vivo studies. While published data have not ment of bone formation [25]. In vitro studies utilizing cancer cell
reported adverse effects of resveratrol in humans, in some animal lines revealed that EGCG induces apoptosis and promotes cell
studies, high dosages (3 g/kg/day in rats) has led to death due to growth arrest by regulating the cell cycle regulatory proteins, acti-
nephrotoxicity [66]. In contrast, several in vitro and in vivo studies vating killer caspases, and down regulating IL-1β and NF-κB [57,
have reported that resveratrol is well-tolerated and relatively non- 90]. However, cell apoptosis was not observed in healthy cells.
toxic [67, 68]. Further studies are warranted to elucidate the Studies performed with osteoblastic cells revealed that green tea
mechanism of action, as well as the dose response safety, of res- increased osteoblast survival and decreased the cell apoptosis due to
veratrol in clinical applications aimed at modulation of inflamma- TNF-α and IL-6 inhibition [91]. Additional findings suggest that
tion. Another major challenge is the low bioavailability due to rapid EGCG inactivates additional pro-inflammatory agents, such as
and extensive metabolism of resveratrol. Approaches that utilize PEG2, nitric oxide (NO), and COX2 [86]. Consistent with these
nanotechnological formulations to control release of resveratrol results, studies performed in rats with induced chronic inflamma-
may help expedite the path of resveratrol to clinical trials. tion demonstrated that the green tea polyphenolic compounds re-
duced chronic inflammation while preserving the bone mass and
3.1.2. Curcumin
microarchitecture [87]. For example, Leong et al. found that green
Curcumin is a polyphenol found in the root of the turmeric
tea reduced the expression of pro-inflammatory agents (IL-1β,
plant, Curcuma longa. Curcumin exhibits anti-infectious, chemo-
Microbubbles: A Novel Strategy for Chemotherapy Current Pharmaceutical Design, 2017, Vol. 23, No. 00 5
TNF-α, and IL-6) and inflammatory cell infiltration in osteoarthri- monocyte chemoattractant protein-1. In vitro studies on exposing
tis mouse model [92]. two types of pancreatic cells (Miapaca-2 and AsPC-1) to proantho-
The toxicity of compounds isolated from green tea has been cyanadin extract for 48 hour found a significant reduction in NF-κB
and IκB kinase-α (IKK-α) in addition to reversal of the epithelial to
assessed in animal models to determine the lethal dose as well as
hematologic and biochemical abnormalities. In one study, it was mesenchymal transition process [107, 108]. Published data utilizing
found that the median lethal dose was above 3-5 g/kg in rats [93]. cardiomyocytes have shown that at low concentrations (5-10
µg/ml), proanthocyanidin possesses antioxidant properties, while at
The modulatory effect of EGCG on bone mineralization and VEGF
activation combined with its effect on down-regulation of inflam- high concentrations, (100-500 µg/ml) proanthocyanidin becomes a
matory cytokines reaffirms the significant potential of green tea pro-oxidant compound, inducing ROS production and causing cell
death [109].
extracts in tissue engineering applications.
3.1.6. Uncaria tomentosa
3.1.4. Omega 3
Uncaria tomentosa is a Peruvian woody vine known as cat’s
Omega 3 is a natural anti-inflammatory compound mainly
found in fish oil with active ingredients of eicosapentaenoic acid claw. The active compounds of this source include diverse arrays of
polyphenols. Uncaria tomentosa has been shown to be effective in
(EPA), docosahexanoic acid (DHA), and poly-unsaturated fatty
the treatment of various diseases including rheumatism, irregular
acids (PUFAs) [94, 95]. Most of the studies of omega 3 have tradi-
tionally focused on cardiovascular diseases, obesity, and diabetes menstruation, tumorigenesis, and kidney problems [110, 111]. Sev-
eral studies have revealed that this natural compound has anti-
showing the potential of EPA and DHA to augment the production
inflammatory properties on the basis that it inhibits TNF-α expres-
of PEG3 and inhibit the transformation of arachidonic acid to
PEG2 [23, 57]. Studies performed in LPS-stimulated mouse micro- sion and NO synthase and suppresses the activation of NF-κB [57,
110]. This observation was consistent with an in vivo study demon-
glial cells assessed the mechanism of action of EPA, DHA, and
strating that an oral dose of Uncaria tomentosa suppressed TNF-α,
PUFAs. The data demonstrated that these three active ingredients of
Omega 3 activate the SIRT1 pathway by inhibiting NF-κB and IL-1α, and IL-1β, IL-4, and IL-17 [111]. Furthermore, the admini-
stration of Uncaria tomentosa for 8 days lowered the expression of
reducing IL-6 and TNF-α expression [96]. Clinical investigations
pro-inflammatory markers including NF-κB, COX1, and COX2
have revealed that patients who receive an omega 3 treatment dem-
onstrated a suppression in arachidonic acid [97, 98]. In addition, it [112-115]. Other studies have shown that Uncaria tomentosa inhib-
its proliferation of tumor cells without causing cell death and im-
was shown that omega 6 activates the choline and ethanolamine
proving cells’ DNA repair [116]. Despite its significant potential,
phosphoglycerides and inhibited NF-κB activation [97, 98]. In
another important study, Turnen et al. found that TNF-α and IL-6 the use of uncaria tomentosa at higher doses (320 µg/ml) is not
recommended due to cytotoxic effects (blocking cell proliferation)
expression in serum decreased in patients who were treated with
and safety issues [110, 113].
omega 3 [95]. Further evidence was demonstrated in a recent in
vitro study showing that PUFA inhibited LPS effect in murine
3.2. Flavonoids
RAW macrophages leading to a reduction in the numbers of M1
macrophages and an increase of M2 macrophages in the adipose Flavonoids are water soluble metabolites abundantly found in
tissue in a mouse model [99]. plants which have shown many health benefits. They are most fa-
mous for their antioxidant, anti-inflammatory, and anti-
A recent report coming out of Mayo Clinic has provided evi-
carcinogenic properties [56, 117]. In the following, we provide a
dence that omega 3 is not toxic in low and moderate dosages [100].
review of four promising flavonoids with potential to mediate in-
In contrast, Sijben and Cader revealed that an n-3 PUFA supple-
flammatory response to biomaterials.
ment depressed immune system due to an alteration in cytokine
production, T-cell proliferation, and T cell-mediated cytotoxicity 3.2.1. 6-Shogaol
[101]. In another study, Woodworth et al. pre-treated mice with a 3 6-shogaol is one of the main compounds extracted from ginger
g/kg EPA + 32.4 g/kg DHA diet for 6-8 weeks before inducing which has been shown to possess anti-inflammatory, anti-
colitis. The histophatology results revealed that EPA and DHA carcinogenic, and anti-oxidant properties due to its inactivation of
pre-treated animals had a higher degree of inflammation and rate of NF-κB and down-regulation of IL-1β in a mouse model [56, 118-
mortally as compared to the control group (regular diet enriched 120]. It has been used to treat neurodegenerative diseases such as
with corn oil or safflower oil). These observations can be related to Alzheimer’s and Parkinson’s due to its anti-neuroinflammatory and
immune system alteration [102]. anti-oxidant properties [121]. In a recent study it was found that
3.1.5. Proanthocyanidins LPS-induced rat astrocytes treated with 6-shogaol showed an im-
provement in neuro-inflammation due to reduction in the levels of
Proanthocyanidins are a class of polyphenolic compounds pre-
IL-1β and IL-6, down-regulation of iNOS and COX2, and inactiva-
sent in the fruits, bark, leaves, and seeds of various plants, which
tion of NF-κB pathway [122]. Furthermore, it has been demon-
possess anti-bacterial, anti-viral, anti-inflammatory, and vasodila-
strated that 6-shogaol blocks the expression of iNOS and COX2
tory properties [26, 103, 104]. The treatment of murine macro-
and inhibits the transcription of NF-κB in LPS-induced macro-
phages with a proanthocyanidin has recently been shown to down-
phages and in a mouse model [119, 123]. The applicability of this
regulate a number of inflammatory cytokines including IL-1β,
compound is not limited to neuro-inflammation. In fact, 6-shogaol
COX2, IL-6, and TNF-α [105]. In addition, in vivo studies have
treatment of rats, in which complete Freund’s adjuvant (CFA) had
revealed that proanthocyanidin augments the expression of IL-4,
been administered to the synovial cavity of the knee, led to a sig-
IL-10, and transforming growth factor β (TGF-β1) while dampen-
nificant reduction in the knee swelling and inflammatory cell infil-
ing the expression of IL-1β, macrophage inflammatory protein 1
tration in the affected area [53]. In the context of cancer therapeu-
(MIP-1), and monocyte chemoattract protein-1 (MCP-1) in a mouse
tics, Shogaol compounds (6-shogaol and 3-phenil-3-shogaol) down-
model of induced arthritis [26, 103].
regulated NF-κB and the associated MMP-9 expression in breast
Proanthocyanidin has a great potential to combat venous and cancer cells while suppressing IL-1β and TNF-α in LPS-induced
capillary diseases as well as tumor formation due to its anti- microglia cells [123, 124]. Studies performed using breast cancer
thrombotic and anti-inflammatory effects. In a recent study in rats cells (MCF-7, dosed with 6-shogaol 39.52 µM), revealed that 6-
with cardiovascular conditions, the oral administration of oli- shoagaol reduces the expression of cancer stem cell markers
gomeric proanthocyanidin was shown to reduce atherosclerosis (CD44+, and CD24-/low) due to the mitotic block and interference
[106]. The macrophage differentiation was controlled through with the self-renewal pathway. Higher concentrations of 6-shoagaol
down-regulation of vascular cell adhesion protein 1 (VCAM-I) and have been shown to be safe for noncancerous cells (HEK 293 and
6 Current Pharmaceutical Design, 2017, Vol. 23, No. 00 Yanez et al.
HaCaT cells treated with 69.97 and 103.84 µM, respectively) [125]. TNF-α, and IFN-γ in addition to suppressing the activation of NF-
Further in vivo studies will be needed to obtain a definitive evalua- κB both in vivo and in vitro [143, 144]. The administration of quer-
tion of toxic effects and clinical potential of 6-shoagol. cetin induced the activation of nuclear factor NRF2 in LPS-induced
human aortic endothelial cells [145]. It has been discovered that
3.2.2. Salicylate (Salycilic Acid or Salicin)
NRF2 protects against inflammation by down-regulating pro-
Salicylate (salycilic acid or salicin), the main component of
inflammatory cytokines [146]. Consistent with this finding, human
aspirin, is a natural compound extracted from white willow bark
intestinal biopsies from inflamed areas were treated with quercetin,
which is and has been used to treat pain, inflammation, fever, and
and the results revealed that quercetin up-regulated secretory leuko-
recently, osteoarthritis and lower back pain [57, 126, 127]. Salicy-
cyte protease inhibitor (Slpi) expression and suppressed TNF-α
late is a non-selective inhibitor of COX1 and COX2 and induces an
[145]. More recent clinical studies revealed that quercetin oral ad-
anti-inflammatory effect in a variety of diseases [127, 128]. A re-
ministration of quercetin to patients with rheumatoid arthritis re-
cent in vitro study has shown that administration of D(-)-salicin
duced TNF-α levels in plasma [147].
down-regulates TNF-α, IL-1β, and IL-6 in LPS-induced inflamma-
The application of quercetin is hampered by deglycosylation
tory macrophages [129]. Consistent with this finding, the intraperi-
limiting the lifespan of this flavonoid. To overcome this limitation,
toneal injection of D(-)-salicin reduced TNF-α, IL-1β, and IL-6
researchers encapsulated quercetin in poly(L-lactic acid) scaffolds
levels and significantly increased IL-10 levels in mice with LPS-
to preserve the antioxidant’s stability properties and more effec-
induced inflammation [129]. In addition, D (-)-salicin was shown to
tively deliver the compound [148]. In light of advances in drug
inhibit the infiltration of neutrophils and macrophages into LPS-
delivery approaches and given the striking potential of this herb in
induced lung tissue, improve the accumulation of nuclear factor
modulating inflammation, further studies are warranted to assess its
erythroid 2-related factor-2 (NRF-2), and reduce oxidative stress
clinical utility in combination with scaffolds in regenerative medi-
[129]. Due to these anti-inflammatory properties, salicylate has
cine.
been used to treat a number of inflammatory diseases. For example,
in a recent study colitis was treated with salicylate by intraperito-
3.3. Triterpenes
neal injection for 7 days leading to suppressed edema, mucosal
damage, and gross bleeding [130]. Another relevant application is Triterpenes are a class of active natural compounds that are
the development of fully bio-absorbable salicylate-base sirolimus- found in leaves, stem bark, fruits, and roots which have been the
eluting stent, which was implanted in a porcine coronary artery. focus of phytochemical investigations. In the following, we review
The authors reported a positive device incorporation without caus- recent in vitro and in vivo studies that used three types of triterpe-
ing excessive thrombotic reaction [131]. The therapeutic use of nes to combat inflammatory diseases.
salicylate, however, faces challenges due to side effects including 3.3.1. Tinospora cordifolia (Guduchi)
gastrointestinal irritation [128, 132, 133]. Studies performed in rats
Tinospora cordifolia (Guduchi) belongs to the Menispermaceae
showed evidence that salicylate (10-100 mM) intestinal irritation is
family and is found in Southeast Asia. Various active ingredients
due to the intestinal epithelial cell permeability [134]. There have
including alkaloids, steroids, diterpenoids, lactones, aliphatics, and
also been isolated reports of toxic side effects associated with the
glycosides can be extracted from different parts of this plant [149].
use of salicylates. As such, future investigations should determine
Published data have shown the potential of tinospora cordifolia to
the efficacy of low-dose therapies.
treat various diseases due to its anti-diabetic, anti-malarial, anti-
3.2.3. Naringin oxidant, anti-allergic, and anti-inflammatory properties [24, 149-
Naringin is a bioflavonoid mainly found in grapefruits and 153]. Diterpenoids, lactones, and aliphatic compounds are respon-
other citrus fruit. Naringin possesses anti-carcinogenic, anti- sible for the anti-inflammatory effects of this plant [149]. Tinosfora
oxidant, anti-inflammatory, lipid-lowering, superoxide scavenging, cordifolia regulates both pro- and anti-inflammatory pathways by
anti-atherogenic, and metal-chelating effects [117, 135]. Recent the activation of various cytokines [153]. In one study, Sannegowda
investigations have revealed that naringin administration sup- et al. found that when rats with an induced form of arthritis were
pressed NF-κB activation and inhibited NO production in both treated with tinosfora cordifolia extract, it down-regulated several
LPS-induced macrophages and LPS-induced mice [136, 137]. A pro-inflammatory cytokines including IL-1β, IL-6, IL-23, TNF-α
number of clinical studies have used naringin to treat inflammatory and MIP-1 [154]. In another recent study, oral delivery of tinosfora
diseases in vivo. For example, using a rat model, investigators have cordofila led to significant down-regulation of iNOS, COX2, and
shown that naringin down-regulates TNF-α and NF-κB levels in intercellular adhesion molecule-1 (ICAM-1) in asthmatic mice
cis-induced striatal injury [135] and kidney injury (gentamicin [155]. Tinosfora cordofila extract (octacosanol) inhibited tumor cell
nephrotoxicity) [138]. In another study, a two-week treatment with proliferation and the angiogenesis of Ehrlich tumor cells implanted
naringin improved swelling, decreased the T-cell numbers, down- in mice through inhibition of NF-κB activation [156].
regulated IL-17A and IL-1β, increased the Treg population, up- Tinosfora cordifolia extract has shown to be pro-osteogenic.
regulated Foxp3 and trans-acting T-cell-specific transcription factor Human osteoblast-like cells and primary rat osteoblastic cells pro-
(GATA-3), and activated IL-10 and IL-4 in mice with induced pol- liferated at a higher rate and accelerated mineral content deposition
yarthritis [117]. The oral administration of naringin has also been when exposed to a Tinosfora cordifolia extract [150, 157]. A recent
demonstrated to inhibit NF-κB in bronchoalveolar lavage fluid and study revealed that osteoblasts enhance mineral deposition when
reduce neutrophil infiltration into the lungs of LPS-induced acute exposed to 12.5-25 µg/ml of tinosfora cordofila. This effect was
lung injury as well as suppress MMP-9 expression in paraquat- measured by monitoring alkaline phosphatase and calcium dep-
induced pulmonary fibrosis in mice [139, 140]. Despite the signifi- sotion in rat primary osteoblast as well as human osteoblast-like
cant benefits of Naringin, this natural compound has shown to MG-63 cells in the presence of Tinosfora cordofila [158]. These
cause several side effects including nausea, anorexia, and vomiting results all together demonstrate the potential of tinosfora cordofila
due to the inappropriate diffusion in the brain [141]. to be used in tissue engineering applications to concurrently en-
3.2.4. Quercetin hance bone repair and alleviate inflammatory response.
Quercetin is a polyphenolic flavonoid mainly found in fruits 3.3.2. Boswellic acid
and vegetables. Quercetin possesses anti-oxidant, anti-carcino- Boswellic acid is a pentacyclic triperpenoid that is extracted
genic, anti-inflammatory [142], and mitochondria protective effects from the resin of the Boswellia serrata tree [159]. Boswellic acid is
[143]. Recent studies have revealed that quercetin administration a combination of the triterpenoids β-boswellic acid, 3-acetyl-β-
prevented the increase of inflammatory cytokines including IL-1β, boswellic acid, 11-keto-β-boswellic acid, and 3-acetyl-11-keto-β-
Microbubbles: A Novel Strategy for Chemotherapy Current Pharmaceutical Design, 2017, Vol. 23, No. 00 7
boswellic acid. It has been used to treat chronic inflammation in in nature and not due to a single cytokine or cellular phenomenon.
rheumatoid arthritis, asthma, ulcerative colitis, and Crohn’s disease The remarkable capability of natural compounds to bind to various
on the basis that it targets NF-κB, signal transducer and activa- sites of multiple interacting molecular targets offers an innovative
tor of transcription 3 (STAT3), androgen receptor (AR), p21, approach to identify and modulate targets in interdependent bio-
death receptor 5 (DR5), and caspase-3 and -8 [159-161]. It has been logical processes such as inflammation, angiogenesis, and tissue
reported that this plant has anti-cancer properties due to its capacity repair. Exploiting the potential of pharmacologically active natural
to inhibit growth and to induce apoptosis [159, 162]. In vitro studies compounds may offer a safe and robust approach to regulate the
have reported that boswellic acid inhibits iNOS activity in LPS- complex signaling network that governs these pathologies
induced macrophages [163]. Other studies have revealed that bos-
wellic acid suppresses NF-κB and STAT in several cancer cell CONFLICT OF INTEREST
lines, including HT-29 colon, SW-620, Colo-205, Hep-2 larynx, The authors declare no conflict of interest.
DU-145 prostate, and PC-3, confirming the anti-cancer activity of
boswellic acid [162]. Animal studies have shown that boswellic ACKNOWLEDGEMENTS
acid leads to reduction in the weight of the tumor-like cells, inhibi- We gratefully acknowledge support from the National Institutes
tion of fibrovascular tissue, and a down-regulation tumor angio- of Health (NIH P20 GM103641), (NIH AR063338), and National
genesis. Science Foundation (NSF 1631439).
Arthritis is another inflammatory disease for which boswellic
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